Project Summary/Abstract HIV is the virus that causes AIDS. HIV/AIDS has claimed and continues to claim millions of human lives world wide, but there are still no effective vaccines to control the pandemics. While our knowledge of HIV pathogenesis has increased during the past few years, we have recently begun to learn more about the devastating effects of HIV infection on the specific immune cells in the gut mucosa. The study proposed here will help us understand the underlying mechanisms for the severe loss of host defense cells in the gut mucosa and pave the way to find new strategies to prevent HIV infection and pathogenesis. From the early acute stages of HIV infection, gut mucosal CD4 T cells are severely and disproportionately affected by the virus. Recent studies show that Th17 cells in the intestinal mucosa are the cells preferentially depleted during HIV infection. Since Th17 cells play an important role in the host defense against extracellular bacteria and fungal infections, the loss of these cells contributes significantly to HIV pathogenesis. However, the reasons for preferential loss of gut-associated Th17 cells during HIV infection are not fully understood. In this application, we hypothesize that unlike Th1 cells, Th17 cells synthesize no or little anti-HIV CCR5 ligands, which render them more sensitive to HIV infection, especially by the CCR5-tropic isolates. To test this hypothesis, we propose to investigate the role of TH17 cells, as compared to Th1 cells, in terms of HIV infectivity and pathogenesis. More specifically, we propose to evaluate the levels of CCR5 chemokine receptor expression in TH17 cells in the peripheral blood and the intestinal mucosa. Chemokine receptors, along with CD4, are required for HIV infection and increased levels of these receptors render the cells more susceptible to HIV infection. We will also evaluate the capacity of Th17 cells to synthesize CCR5 ligands (MIP-1Beta, MIP-1alpha and RANTES), which are known to have potent anti-viral activity against CCR5-tropic isolates, the dominant viruses currently circulating worldwide. Subsequently, we will determine the susceptibility of TH17 cells to in vitro challenge by CCR5 tropic vs. CXCR4 tropic HIV viruses. These in vitro data will then be correlated to the levels of Th17 cells ex vivo that still remain and are capable of expressing CCR5 ligands and other cytokines in different groups of HIV-infected subjects as well as HIV-uninfected subjects.